Approximately 40% of patients with activated B cell (ABC) subtype of diffuse large B cell lymphoma DLBCL relapse or are not curable with current therapies. The mechanism through which ABC-DLBCLs are resistant to current therapies are unknown but may be linked to the particular spectrum of somatic mutations in these tumors, which are in concert with complex growth signals provided by the lymphoid tumor microenvironment (Ly-TME). Many of the hallmark ABC-DLBCL mutations result in constitutive activation of B cell receptor (BCR) and Toll like receptor (TLR) pathways in these malignant immune cells. Hence these pathways are emerging as a source of therapeutic targets for the treatment of ABC-DLBCLs. However, to date, existing BCR pathway inhibitors such as those targeting Bruton?s tyrosine kinase (BTK) are active in a limited subset of patients and only for a short duration (few months), causes of which are unknown. The substantial differences in response rates and response duration between ABC-DLBCL patients reflect the variable dependencies on BCR and TLR signaling and/or differential regulation by the Ly-TME. Therefore, Ly-TME seems essential for ABC-DLBCLs in spite of constitutive action of signaling pathways. ABC-DLBCLs have multiple cooperative and feed-back, and bypass signaling pathways that promote tumor survival and personalized therapy will require combination therapeutics to adequately suppress these networks. Unfortunately, the impact of Ly-TME on these signaling pathways in ABC-DLBCLs and, consequently, on the efficacy of targeted therapeutics are poorly understood. Therefore, the objective of this R01 is to develop an experimental therapeutics technology with Ly-TME and determine the role of Ly-TME on ABC-DLBCL survival, signaling, and response to pathway inhibitors of the Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) paracaspase. By integrating the results of R01, the team will determine the role of Ly-TME in BCR-MALT1 and TLR signaling in ABC- DLBCL and determine a more refined dosing scheme. Mechanisms from this R01 will increase ?predictive power? of MALT1 inhibitors, and provide mechanistic clues towards resistance to MALT1 inhibitors, and discover combinatorial therapy to overcome resistance.